This thesis is concerned with the neurocircuitry that underpins the cardiovascular response to exercise, which has thus far remained incompletely understood. Small animal studies have provided clues, but with the advent of functional neurosurgery, it has now been made possible to translate these findings to humans. Chapter One reviews the background to the studies in this thesis. Our current understanding of the cardiovascular response to exercise is considered, followed by a discussion on the anatomy and function of various brain nuclei. In particular, the rationale for targeting the periaqueductal grey (PAG) and the subthalamic nucleus (STN) is reviewed. Chapter Two reviews the use of deep brain stimulation (DBS), in which deep brain stimulating electrodes are implanted into various brain nuclei in humans, in order to treat chronic pain and movement disorders. This technique not only permits direct electrical stimulation of the human brain, but also gives the opportunity to record the neural activity from different brain regions during a variety of cardiovascular experiments. This chapter also gives a detailed methodological description of the experimental techniques performed in the studies in this thesis. Chapter Three identifies the cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery. It shows for the first time in humans that the exercise pressor reflex is associated with significantly increased neural activity in the dorsal PAG. The other sites investigated, which had previously been identified as cardiovascular active in both animals and humans, seem not to have a role in the integration of this reflex. Chapter Four investigates whether changes in exercise intensity affect the neurocircuitry involved in the exercise pressor reflex. It demonstrates that the neural activity in the PAG is graded to increases in exercise intensity and corresponding increases in arterial blood pressure. This chapter also provides evidence to suggest that neural activity in the STN corresponds to the cardiovascular changes evoked by the remote ischaemic preconditioning stimulus in humans. Chapter Five identifies the cardiovascular neurocircuitry involved during changes in central command during isometric exercise at constant muscle tension using muscle vibration. It shows that, in humans, central command is associated with significantly decreased neural activity in the STN. Furthermore, the STN is graded to the perception of the exercise task, i.e. the degree of central command. The other sites investigated appear not to have as significant a role in the integration of central command during the light exercise task that was undertaken. Chapter Six studies the changes in muscle sympathetic nerve activity (MSNA) during stimulation of various brain nuclei in humans. Regrettably, the results presented in this chapter are not convincing enough to support the hypothesis that stimulation of particular subcortical structures corresponds to changes in MSNA. However, the cardiovascular changes that were recorded during stimulation of the different subcortical structures are congruous with previous studies in both animals and humans. Chapter Seven presents a brief summary of the findings in this thesis.

INTRODUÇÃO: Pacientes com síndrome metabólica (SMet) apresentam aumento na atividade nervosa simpática muscular (ANSM) e diminuição no ganho do controle barorreflexo arterial (CBR). E, a apnéia obstrutiva do sono (AOS), uma comorbidade frequentemente encontrada em pacientes com SMet, exacerba essas disfunções autonômicas. Sabe-se que a incidência dos disparos e o padrão oscilatório da ANSM dependem do ganho (sensibilidade) e do tempo de retardo (latência) do CBR da ANSM (CBRANSM). Contudo, o padrão oscilatório da ANSM e o tempo de retardo do CBRANSM em pacientes com SMet associada ou não à AOS são desconhecidos. Além disso, estudos prévios demonstram que o treinamento físico associado à dieta hipocalórica (TF+D) diminui a incidência dos disparos da ANSM e aumenta o ganho do CBR em pacientes com SMet. No entanto, os efeitos de TF+D no padrão oscilatório da ANSM e no ganho e tempo de retardo do CBRANSM em pacientes com SMet associado ou não a AOS permanecem desconhecidos. MÉTODOS: Foram estudados quarenta e quatro pacientes com SMet (critérios do ATP III), sem uso de medicamentos, que foram divididos em dois grupos de acordo com a presença da AOS (SMet-AOS, n=23 e SMet+AOS, n=21). Um grupo controle saudável (n=12) foi, também, incluído no estudo. Para avaliar o efeito da intervenção, os pacientes foram divididos consecutivamente em quatro grupos: 1- Sedentário sem AOS (SMet-AOS Sed, n=10); 2- Sedentário com AOS (SMet+AOS Sed, n=10); 3- TF+D sem AOS (SMet-AOS TF+D, n=13) e; 4- TF+D com AOS (SMet+AOS TF+D, n=11). Os grupos TF+D foram submetidos ao treinamento físico aeróbio (40 min, 3 vezes por semana) associado à dieta hipocalórica (-500 kcal/dia) durante quatro meses e os grupos sedentários não realizaram a intervenção (TF+D) e somente receberam orientações clínicas. A AOS foi determinada através do índice de apneia e hipopneia (IAH) >15 eventos/hora (polissonografia). A ANSM (microneurografia), pressão arterial (batimento a batimento, método oscilométrico), padrão oscilatório da ANSM (relação dos componentes de baixa frequência-BF, e alta frequência-AF da ANSM, BFANSM/AFANSM, análise espectral autorregressivo monovariada) e o CBRANSM espontâneo (ganho e tempo de retardo, análise espectral autorregressivo bivariada) foram avaliados durante o repouso na posição deitada por 10 minutos. RESULTADOS: No período pré-intervenção, os pacientes com SMet-AOS e SMet+AOS apresentaram redução no BFANSM/AFANSM (P=0,01 e P<0,001, respectivamente) e no ganho do CBRANSM (P=0,01 e P<0,001, respectivamente), em comparação com o grupo Controle. E, os pacientes com SMet+AOS apresentaram menor BFANSM/AFANSM (P=0,02) e ganho do CBRANSM (P<0,001) em comparação com SMet-AOS. Ainda, o tempo de retardo do CBRANSM estava aumentado no grupo SMet+AOS em comparação com os grupos SMet-AOS e Controle (P=0,01 e P<0,001, respectivamente). Após a intervenção TF+D, ambos os grupos SMet-AOS e SMet+AOS apresentaram redução do peso corporal, circunferência abdominal e pressão arterial sistólica e aumento consumo de oxigênio no pico do exercício. Nos pacientes com SMet-AOS, o TF+D aumentou o BFANSM/AFANSM (P<0,05) e o ganho do CBRANSM (P<0,01). Nos pacientes com SMet+AOS, o TF+D aumentou o nível de saturação mínima de O2 (P=0,02) durante a polissonografia, o BFANSM/AFANSM (P=0,001) e o ganho do CBRANSM (P<0,01) e, diminuiu o IAH (P<0,01) durante a polissonografia e o tempo de retardo do CBRANSM (P=0,01). Nenhuma alteração foi observada em ambos os grupos sedentários. CONCLUSÕES: O TF+D aumenta o padrão oscilatório da ANSM e o ganho do CBRANSM em pacientes com SMet, independentemente da presença da AOS. No entanto, este efeito é mais pronunciado em pacientes com SMet+AOS, já que após a intervenção o tempo de retardo do CBRANSM foi também diminuído nestes pacientes / INTRODUCTION: Patients with metabolic syndrome (MetS) have increased muscle sympathetic nerve activity (MSNA) and decreased arterial baroreflex control (BRC). Obstructive sleep apnea (OSA), a comorbidity often found in patients with MetS, exacerbates these autonomic dysfunctions. It is known that burst incidence and the oscillatory pattern of MSNA depend on the gain (sensitivity) and the time delay (latency) of BRC of MSNA (BRCMSNA). However, the oscillatory pattern of MSNA and the time delay of BRCMSNA in patients with MetS either with or without OSA are unknown. Moreover, previous studies have shown that exercise training associated with hypocaloric diet (ET+D) decreases the burst incidence of MSNA and increases the gain of BRC in patients with MetS. However, the effects of ET+D on the oscillatory pattern of MSNA and on the gain and time delay of BRCMSNA in patients with MetS with or without OSA remain unknown. METHODS: Forty-four never-treated MetS patients (ATP III criteria) were allocated in two groups according to the presence of OSA (MetS-OSA, n=23 and MetS+OSA, n=21). A healthy control group (n=12) was also included in the study. To evaluate the effect of the intervention, patients were consecutively divided into four groups: 1- Sedentary without OSA (MetS-OSA Sed, n=10); 2- Sedentary with OSA (MetS+OSA Sed, n=10); 3- ET+D without OSA (MetS-OSA TF+D, n=13) and 4- ET+D with OSA (MetS+OSA ET+D, n=11). ET+D groups were submitted to aerobic exercise (40 min, 3 times per week) associated to hypocaloric diet (-500 kcal / day) for four months and sedentary groups did not perform the intervention (ET+D) and only received clinical orientations. OSA was determined by the apnea-hypopnea index (AHI) >15 events/hour (polysomnography). The MSNA (microneurography), blood pressure (beat-to-beat basis, oscillometry method), oscillatory pattern of MSNA (relationship of the components of low frequency - LF, and high frequency - HF of MSNA, LFMSNA/HFMSNA, monovariate autoregressive spectral analysis) and spontaneous BRCMSNA (gain and time delay, bivariate autoregressive spectral analysis) were evaluated during rest at lying position for 10 min. RESULTS: In the pre-intervention period, patients with MetS-OSA and MetS+OSA showed reduced LFMSNA/HFMSNA (P=0.01 and P<0.001, respectively) and gain of BRCMSNA (P=0.01 and P<0.001, respectively) compared to Control group. And, the patients with MetS+OSA had lower LFMSNA/HFMSNA (P=0.02) and gain of BRCMSNA (P<0.001) compared to MetS- OSA. The time delay of BRCMSNA was higher in MetS+OSA group compared to MetS-OSA and Control groups (P=0.01 and P<0.001, respectively). After ET+D, both groups MetS-OSA and MetS+OSA decreased body weight, waist circumference and systolic blood pressure and increased peak oxygen uptake during exercise. In patients with MetS-OSA, the ET+D increased LFMSNA/HFMSNA (P<0.05) and the gain of BRCMSNA (P<0.01). In patients with MetS+OSA, ET+D increased minimum oxygen saturation level (P=0.02) during polysomnography, the LFMSNA/HFMSNA (P=0.001) and the gain of BRCMSNA (P<0.01) and decresed AHI (P<0.01) during polysomnography and the time delay of BRCMSNA (P=0.01). No alterations were observed in both sedentary groups. CONCLUSION: ET+D increase the oscillatory pattern of MSNA and the gain of BRCMSNA in patients with MetS, regardless of the presence of OSA. However, this effect is more pronounced in patients with MetS+OSA, since after intervention the time delay of BRCMSNA was also diminished in these patients

INTRODUÇÃO: Pacientes com síndrome metabólica (SMet) apresentam aumento na atividade nervosa simpática muscular (ANSM) e diminuição no ganho do controle barorreflexo arterial (CBR). E, a apnéia obstrutiva do sono (AOS), uma comorbidade frequentemente encontrada em pacientes com SMet, exacerba essas disfunções autonômicas. Sabe-se que a incidência dos disparos e o padrão oscilatório da ANSM dependem do ganho (sensibilidade) e do tempo de retardo (latência) do CBR da ANSM (CBRANSM). Contudo, o padrão oscilatório da ANSM e o tempo de retardo do CBRANSM em pacientes com SMet associada ou não à AOS são desconhecidos. Além disso, estudos prévios demonstram que o treinamento físico associado à dieta hipocalórica (TF+D) diminui a incidência dos disparos da ANSM e aumenta o ganho do CBR em pacientes com SMet. No entanto, os efeitos de TF+D no padrão oscilatório da ANSM e no ganho e tempo de retardo do CBRANSM em pacientes com SMet associado ou não a AOS permanecem desconhecidos. MÉTODOS: Foram estudados quarenta e quatro pacientes com SMet (critérios do ATP III), sem uso de medicamentos, que foram divididos em dois grupos de acordo com a presença da AOS (SMet-AOS, n=23 e SMet+AOS, n=21). Um grupo controle saudável (n=12) foi, também, incluído no estudo. Para avaliar o efeito da intervenção, os pacientes foram divididos consecutivamente em quatro grupos: 1- Sedentário sem AOS (SMet-AOS Sed, n=10); 2- Sedentário com AOS (SMet+AOS Sed, n=10); 3- TF+D sem AOS (SMet-AOS TF+D, n=13) e; 4- TF+D com AOS (SMet+AOS TF+D, n=11). Os grupos TF+D foram submetidos ao treinamento físico aeróbio (40 min, 3 vezes por semana) associado à dieta hipocalórica (-500 kcal/dia) durante quatro meses e os grupos sedentários não realizaram a intervenção (TF+D) e somente receberam orientações clínicas. A AOS foi determinada através do índice de apneia e hipopneia (IAH) >15 eventos/hora (polissonografia). A ANSM (microneurografia), pressão arterial (batimento a batimento, método oscilométrico), padrão oscilatório da ANSM (relação dos componentes de baixa frequência-BF, e alta frequência-AF da ANSM, BFANSM/AFANSM, análise espectral autorregressivo monovariada) e o CBRANSM espontâneo (ganho e tempo de retardo, análise espectral autorregressivo bivariada) foram avaliados durante o repouso na posição deitada por 10 minutos. RESULTADOS: No período pré-intervenção, os pacientes com SMet-AOS e SMet+AOS apresentaram redução no BFANSM/AFANSM (P=0,01 e P<0,001, respectivamente) e no ganho do CBRANSM (P=0,01 e P<0,001, respectivamente), em comparação com o grupo Controle. E, os pacientes com SMet+AOS apresentaram menor BFANSM/AFANSM (P=0,02) e ganho do CBRANSM (P<0,001) em comparação com SMet-AOS. Ainda, o tempo de retardo do CBRANSM estava aumentado no grupo SMet+AOS em comparação com os grupos SMet-AOS e Controle (P=0,01 e P<0,001, respectivamente). Após a intervenção TF+D, ambos os grupos SMet-AOS e SMet+AOS apresentaram redução do peso corporal, circunferência abdominal e pressão arterial sistólica e aumento consumo de oxigênio no pico do exercício. Nos pacientes com SMet-AOS, o TF+D aumentou o BFANSM/AFANSM (P<0,05) e o ganho do CBRANSM (P<0,01). Nos pacientes com SMet+AOS, o TF+D aumentou o nível de saturação mínima de O2 (P=0,02) durante a polissonografia, o BFANSM/AFANSM (P=0,001) e o ganho do CBRANSM (P<0,01) e, diminuiu o IAH (P<0,01) durante a polissonografia e o tempo de retardo do CBRANSM (P=0,01). Nenhuma alteração foi observada em ambos os grupos sedentários. CONCLUSÕES: O TF+D aumenta o padrão oscilatório da ANSM e o ganho do CBRANSM em pacientes com SMet, independentemente da presença da AOS. No entanto, este efeito é mais pronunciado em pacientes com SMet+AOS, já que após a intervenção o tempo de retardo do CBRANSM foi também diminuído nestes pacientes / INTRODUCTION: Patients with metabolic syndrome (MetS) have increased muscle sympathetic nerve activity (MSNA) and decreased arterial baroreflex control (BRC). Obstructive sleep apnea (OSA), a comorbidity often found in patients with MetS, exacerbates these autonomic dysfunctions. It is known that burst incidence and the oscillatory pattern of MSNA depend on the gain (sensitivity) and the time delay (latency) of BRC of MSNA (BRCMSNA). However, the oscillatory pattern of MSNA and the time delay of BRCMSNA in patients with MetS either with or without OSA are unknown. Moreover, previous studies have shown that exercise training associated with hypocaloric diet (ET+D) decreases the burst incidence of MSNA and increases the gain of BRC in patients with MetS. However, the effects of ET+D on the oscillatory pattern of MSNA and on the gain and time delay of BRCMSNA in patients with MetS with or without OSA remain unknown. METHODS: Forty-four never-treated MetS patients (ATP III criteria) were allocated in two groups according to the presence of OSA (MetS-OSA, n=23 and MetS+OSA, n=21). A healthy control group (n=12) was also included in the study. To evaluate the effect of the intervention, patients were consecutively divided into four groups: 1- Sedentary without OSA (MetS-OSA Sed, n=10); 2- Sedentary with OSA (MetS+OSA Sed, n=10); 3- ET+D without OSA (MetS-OSA TF+D, n=13) and 4- ET+D with OSA (MetS+OSA ET+D, n=11). ET+D groups were submitted to aerobic exercise (40 min, 3 times per week) associated to hypocaloric diet (-500 kcal / day) for four months and sedentary groups did not perform the intervention (ET+D) and only received clinical orientations. OSA was determined by the apnea-hypopnea index (AHI) >15 events/hour (polysomnography). The MSNA (microneurography), blood pressure (beat-to-beat basis, oscillometry method), oscillatory pattern of MSNA (relationship of the components of low frequency - LF, and high frequency - HF of MSNA, LFMSNA/HFMSNA, monovariate autoregressive spectral analysis) and spontaneous BRCMSNA (gain and time delay, bivariate autoregressive spectral analysis) were evaluated during rest at lying position for 10 min. RESULTS: In the pre-intervention period, patients with MetS-OSA and MetS+OSA showed reduced LFMSNA/HFMSNA (P=0.01 and P<0.001, respectively) and gain of BRCMSNA (P=0.01 and P<0.001, respectively) compared to Control group. And, the patients with MetS+OSA had lower LFMSNA/HFMSNA (P=0.02) and gain of BRCMSNA (P<0.001) compared to MetS- OSA. The time delay of BRCMSNA was higher in MetS+OSA group compared to MetS-OSA and Control groups (P=0.01 and P<0.001, respectively). After ET+D, both groups MetS-OSA and MetS+OSA decreased body weight, waist circumference and systolic blood pressure and increased peak oxygen uptake during exercise. In patients with MetS-OSA, the ET+D increased LFMSNA/HFMSNA (P<0.05) and the gain of BRCMSNA (P<0.01). In patients with MetS+OSA, ET+D increased minimum oxygen saturation level (P=0.02) during polysomnography, the LFMSNA/HFMSNA (P=0.001) and the gain of BRCMSNA (P<0.01) and decresed AHI (P<0.01) during polysomnography and the time delay of BRCMSNA (P=0.01). No alterations were observed in both sedentary groups. CONCLUSION: ET+D increase the oscillatory pattern of MSNA and the gain of BRCMSNA in patients with MetS, regardless of the presence of OSA. However, this effect is more pronounced in patients with MetS+OSA, since after intervention the time delay of BRCMSNA was also diminished in these patients

Hintergrund: Die chronisch obstruktive Lungenerkrankung (COPD) ist eine der Haupttodesursachen weltweit. Eine gesteigerte Aktivität des sympathischen Nervensystems wird als wesentlicher pathophysiologischer Aspekt vermutet. Grundsätze: Die vorliegende Arbeit untersuchte die muskelsympathische Nervenaktivität (MSNA) und die Baroreflex-Sensitivität bei COPD-Patienten und gesunden Probanden in Ruhe sowie unter moderater körperlicher Belastung. Ergebnisse: COPD-Patienten zeigten in Ruhe eine signifikant gesteigerte MSNA sowie eine signifikant verminderte Baroreflex-Sensitivität. Diese Ergebnisse bestätigen die Resultate vorausgegangener Publikationen der Arbeitsgruppe. In der vorliegenden Arbeit konnte erstmals ein signifikanter Anstieg der MSNA unter moderater statischer Belastung bei COPD-Patienten nachgewiesen werden. Fazit: In der vorliegenden Arbeit konnte erstmals eine Korrelation zwischen sympatho-vagaler Imbalance und verminderter körperlicher Leistungsfähigkeit bei COPD-Patienten nachgewiesen werden. Eine Modifikation der neuro-humoralen Aktivität bei COPD-Patienten könnte in Zukunft eine Rolle in der Behandlung der COPD spielen und sollte in größeren, randomisierten Studien untersucht werden.